Comprehensive exploration of chemical space using trisubstituted carboranes

Abstract

A total of 42 trisubstituted carboranes categorised into five scaffolds were systematically designed and synthesized by exploiting the different reactivities of the twelve vertices of o-, m-, and p-carboranes to cover all directions in chemical space. Significant inhibitors of hypoxia inducible factor transcriptional activitay were mainly observed among scaffold V compounds (e.g., Vi–m, and Vo), whereas anti-rabies virus activity was observed among scaffold V (Va–h), scaffold II (IIb–g), and scaffold IV (IVb) compounds. The pharmacophore model predicted from compounds with scaffold V, which exhibited significant anti-rabies virus activity, agreed well with compounds IIb–g with scaffold II and compound IVb with scaffold IV. Normalized principal moment of inertia analysis indicated that carboranes with scaffolds I–V cover all regions in the chemical space. Furthermore, the first compounds shown to stimulate the proliferation of the rabies virus were found among scaffold V carboranes.

Advances in Electrochemiluminescence Biosensors Based on DNA Walkers

“…The acquisition of information in the complex biological systems is an effective way to investigate life activities. Nucleic acids, [46] proteins [47] and small biological molecules, [48] as integral components of living organisms, have extremely important roles in the field of information transfer, catalysis, and biological metabolism of living organisms. Because the tiny change of their abnormal levels is closely related to certain human diseases, how to achieve sensitive and accurate determination of these substances has become a major challenge.…”

Molecular Property Diagnostic Suite Compound Library (MPDS-CL): a structure-based classification of the chemical space

“…In drug/molecular design, the structural similarity is of paramount importance and any effort which structurally and systematically divide the chemical space will be of outstanding interest [1][2][3][4][5]. The need for developing new chemical libraries is of fundamental importance in the current scenario to systematize the process of covering huge chemical space and tapping its potential in multifarious applications in science and technology [6][7][8][9][10]. Such an effort will help to qualitatively and quantitatively estimate and assess the structural similarity and chemical diversity which will be of utility in mining the chemical/biological property space [11][12][13].…”

“…While there are a large number of databases depicting the chemical structures, to our knowledge attempts towards the structural classi cation of compounds are scarce. The recent progress made in the synthesis and the growing need for novel chemical entities together push for an urgent need to scale up the existing methods and design new methods in developing elegant technologies for making the best use of deciphering the structure-property relationships from the chemical space [8][9][10][11][12]. The ultimate goal in all these attempts is to nd out the molecule(s) with most desirable properties, e.g., drugs, catalysts, agrochemicals, etc.…”

Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90–Heat Shock Factor 1 Interaction

“…Various drug candidates have been reported, including estrogen receptor agonists, HSP60 inhibitors, − COX-2 inhibitors, and vitamin D receptor ligands . We previously constructed a compound library consisting of tri- or disubstituted carboranes with benzyl and i -butyl groups as Phe and Leu mimics respectively, based on chemical space exploration . In this library, several di- and trisubstituted para -carboranes, such as 1 and 2a (Figure ), showed potent inhibitory activity against the intracellular transcription of hypoxia-inducible factor 1 (HIF-1).…”

“…To elucidate the effect of carboranes on HIF-1 transcriptional activity and cancer cell proliferation, we next performed a cell-based reporter gene assay using hypoxia response element (HRE)-dependent luciferase-transfected HeLa cells and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, respectively.…”